title: In vitro structure-activity relationships of aplysinopsin analogs and their in vivo evaluation in the chick anxiety-depression model.
abstract: Aplysinopsins are tryptophan-derived natural products that have been isolated from a variety of marine organisms and have been shown to possess a range of biological activities. In vitro receptor binding assays showed that of the 12 serotonin receptor subtypes, analogues showed a high affinity for the 5-HT2B and 5-HT2C receptor subtypes, with selectivity for 5-HT2B over 5-HT2C. While no conclusions could be drawn about the number and position of N-methylations, bromination at C-4 and C-5 of the indole ring resulted in greater binding affinities, with Ki's as low as 35 nM. This data, combined with previous knowledge of the CNS activity of aplysinopsin analogs, suggested that these compounds may have potential as leads for antidepressant drugs. Compounds 3c, 3u, and 3x were evaluated in the chick anxiety-depression model to assess their in vivo efficacy. Compound 3c showed a modest antidepressant effect at a dose of 30 nM/kg in the animal model.
authors.affiliation: Department of Pharmacognosy, University of Mississippi, PO Box 1848, University, MS 38677-1848, USA.
authors.forename: Kevin
authors.initials: K
authors.lastname: Lewellyn
authors.forename: Dobroslawa
authors.initials: D
authors.lastname: Bialonska
authors.forename: Melissa J
authors.initials: MJ
authors.lastname: Loria
authors.forename: Stephen W
authors.initials: SW
authors.lastname: White
authors.forename: Kenneth J
authors.initials: KJ
authors.lastname: Sufka
authors.forename: Jordan K
authors.initials: JK
authors.lastname: Zjawiony
mesh_terms: D000818:Animals; D000928:Antidepressive Agents / Q000737:chemistry* / Q000494:pharmacology* / Q000627:therapeutic use; D001007:Anxiety / Q000188:drug therapy; D001522:Behavior, Animal / Q000187:drug effects; D002645:Chickens; D003863:Depression / Q000188:drug therapy; D004195:Disease Models, Animal; D006801:Humans; D008995:Monoamine Oxidase / Q000737:chemistry / Q000378:metabolism; D011485:Protein Binding / Q000187:drug effects; D044403:Receptor, Serotonin, 5-HT2B / Q000737:chemistry / Q000378:metabolism; D044405:Receptor, Serotonin, 5-HT2C / Q000737:chemistry / Q000378:metabolism; D013329:Structure-Activity Relationship; D014364:Tryptophan / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use
chemical_list: D000928:Antidepressive Agents; D044403:Receptor, Serotonin, 5-HT2B; D044405:Receptor, Serotonin, 5-HT2C; C015685:aplysinopsin; D014364:Tryptophan; D008995:Monoamine Oxidase
keywords: Aplysinopsin; Depression; Monoamine oxidase; Natural products; Serotonin